The influence of viral genotypes and rejection episodes on the recurrence of hepatitis C after liver transplantation

Purpose. The aim of this study was to report the influence of hepatitis C virus (HCV) genotype and rejection episodes on the outcome of orthotopic liver transplantation (OLT), hepatitis recurrence, and progression to graft cirrhosis after OLT. Methods. Fifty-three patients who all had undergone OLT for end-stage liver cirrhosis were selected for this study. Hepatitis C genotype was determined. Recurrent hepatitis and rejection were diagnosed based on elevated liver function tests and a liver biopsy. Results. The patients were followed up for a mean of 51.9 +/- 34.3 months. The cumulative survival rate was no different in OLT for hepatitis C and OLT for all other liver diseases. After OLT, serum HCV RNA was detected in 93%. Histological recurrence occurred in 85% of all patients. The 1-, 3-, and 5-year recurrence rates were 48%, 77%, and 85%, respectively. Of the 41 patients with recurrent hepatitis C, 4 (10%) had cirrhosis, 18 (44%) had hepatitis with fibrosis, and 91 (46%) had hepatitis without fibrosis at the end of follow-up. A total of 32% of the patients were infected by HCV genotype 1b and 68% by other HCV genotypes. The recurrence rates were significantly higher in patients infected with genotype 1b than in those with other genotypes (p = 0.04). Twenty of 48 patients (42%) experienced acute rejection. There was a strong association between the number of rejection episodes and the incidence of HCV-related cirrhosis (p < 0.01). Conclusion. Our findings showed the genotype 1b to result in a higher recurrence rate after OLT. On the other hand, rejection episodes were associated with a more rapid progression to graft cirrhosis.

Bayesian inferences on the recent island colonization history by the bird Zosterops lateralis lateralis

The founding of new populations by small numbers of colonists has been considered a potentially important mechanism promoting evolutionary change in island populations. Colonizing species, such as members of the avian species complex Zosterops lateralis, have been used to support this idea. A large amount of background information on recent colonization history is available for one Zosterops subspecies, Z. lateralis lateralis, providing the opportunity to reconstruct the population dynamics of its colonization sequence. We used a Bayesian approach to combine historical and demographic information available on Z. l. lateralis with genotypic data from six microsatellite loci, and a rejection algorithm to make simultaneous inferences on the demographic parameters describing the recent colonization history of this subspecies in four southwest Pacific islands. Demographic models assuming mutation–drift equilibrium or a large number of founders were better supported than models assuming founder events for three of four recently colonized island populations. Posterior distributions of demographic parameters supported (i) a large stable effective population size of several thousands individuals with point estimates around 4000–5000; (ii) a founder event of very low intensity with a large effective number of founders around 150–200 individuals for each island in three of four islands, suggesting the colonization of those islands by one flock of large size or several flocks of average size; and (iii) a founder event of higher intensity on Norfolk Island with an effective number of founders around 20 individuals, suggesting colonization by a single flock of moderate size. Our inferences on demographic parameters, especially those on the number of founders, were relatively insensitive to the precise choice of prior distributions for microsatellite mutation processes and demographic parameters, suggesting that our analysis provides a robust description of the recent colonization history of the subspecies.

Nitrogen removal from sludge digester liquids by nitrification/denitrification or partial nitritation/anammox: environmental and economical considerations

In wastewater treatment plants with anaerobic sludge digestion, 15-20% of the nitrogen load is recirculated to the main stream with the return liquors from dewatering. Separate treatment of this ammonium-rich digester supernatant significantly reduces the nitrogen load of the activated sludge system. Two biological applications are considered for nitrogen elimination: (i) classical autotrophic nitrification/heterotrophic denitrification and (ii) partial nitritation/autotrophic anaerobic ammonium oxidation (anammox). With both applications 85-90% nitrogen removal can be achieved, but there are considerable differences in terms of sustainability and costs. The final gaseous products for heterotrophic denitrification are generally not measured and are assumed to be nitrogen gas (N-2). However, significant nitrous oxide (N2O) production can occur at elevated nitrite concentrations in the reactor. Denitrification via nitrite instead of nitrate has been promoted in recent years in order to reduce the oxygen and the organic carbon requirements. Obviously this achievement turns out to be rather disadvantageous from an overall environmental point of view. On the other hand no unfavorable intermediates are emitted during anaerobic ammonium oxidation. A cost estimate for both applications demonstrates that partial nitritation/anammox is also more economical than classical nitrification/denitrification. Therefore autotrophic nitrogen elimination should be used in future to treat ammonium-rich sludge liquors.

Establishment of metanephros transplantation in mice highlights contributions by both nephrectomy and pregnancy to developmental progression

Background: It has been demonstrated that embryonic kidneys (metanephroi) xenotransplanted into the omentum of adult recipients continue to develop and display immune protection due to their more nave immune presentation. To date, this has been achieved using rat, pig and human metanephroi, with unilateral nephrectomy (UNX) of recipient rats a requisite of renal development. The aim of this study was to adapt this approach for use in mice and examine the parameters affecting successful onward development in this species. Methods: Metanephroi at embryonic age (E) 13.5 were transplanted either onto the body wall, abdominal fat pads or omentum of recipient isogenic C57/Bl6 mice using either sutures or polyglycolic acid mesh. Having established greatest success with polyglycolic acid mesh on the body wall, E12.5 and 15.5 days metanephroi from C57/Bl6 mice were then transplanted onto the body wall of control (non-pregnant non-UNX), UNX or 12.5 days post-coitum pregnant isogenic recipients. After 7 days, implanted tissue was harvested and examined using histology and immunohistochemistry for markers of renal maturation. The mean number of S-shaped bodies and glomeruli per section were recorded and statistically analysed for significant differences between all recipient groups and untransplanted metanephroi. The degree of development was scored qualitatively. Results: Transplanted E12.5 metanephroi developed S-shaped bodies and glomeruli in all recipient groups, although there were statistically higher numbers of S-shaped bodies in UNX (n = 2) and pregnant recipients (n = 9) than in control recipients (n = 4). Continued development, as indicated by mature vascularized glomeruli, was only observed in those E15.5 metanephroi transplanted into pregnant recipients (n = 11) with a 15.5-fold increase in S-shaped bodies and 4-fold increase in glomeruli compared with control transplants (n = 12). Conclusions: We have successfully established metanephros transplantation in mice and demonstrated enhancement of onward development of E12.5 metanephroi in response to both pregnancy and UNX. Using E15.5 metanephroi, continued development only occurred in pregnant recipients, implying pregnancy provides an environment conducive to continued organogenesis. This murine assay, when coupled with transgenically-tagged strains of mice, will allow the investigation of the relative contribution of donor and recipient cells to this process. Copyright (C) 2005 S. Karger AG, Basel.

Evaluation of cosmic ray rejection algorithms on single-shot exposures

To maximise data output from single-shot astronomical images, the rejection of cosmic rays is important. We present the results of a benchmark trial comparing various cosmic ray rejection algorithms. The procedures assess relative performances and characteristics of the processes in cosmic ray detection, rates of false detections of true objects, and the quality of image cleaning and reconstruction. The cosmic ray rejection algorithms developed by Rhoads (2000, PASP, 112, 703), van Dokkum (2001, PASP, 113, 1420), Pych (2004, PASP, 116, 148), and the IRAF task xzap by Dickinson are tested using both simulated and real data. It is found that detection efficiency is independent of the density of cosmic rays in an image, being more strongly affected by the density of real objects in the field. As expected, spurious detections and alterations to real data in the cleaning process are also significantly increased by high object densities. We find the Rhoads' linear filtering method to produce the best performance in the detection of cosmic ray events; however, the popular van Dokkum algorithm exhibits the highest overall performance in terms of detection and cleaning.

Quantifying aphasic people's social lives in the context of non-aphasic peers

Background: Developing the knowledge base on the impact of aphasia on people's social lives has become increasingly important in recent times to further our understanding of the broad consequences of communication disability and thus provide appropriate services. Past research clearly indicates that relationships and social activities with family members and others undergo change with the onset of aphasia in an individual, however more evidence of a quantitative nature would be beneficial. Aims: The current research furthers our knowledge by quantifying chronically aphasic older people's regular social contacts and social activities, and places them in context by comparing them with healthy older people of similar age and education. Methods & Procedures: A total of 30 aphasic participants aged 57 to 88 years, and 71 non-aphasic controls aged 62 to 98 years were interviewed by a speech and language therapist using self-report measures of Social Network Analysis (Antonucci & Akiyama, 1987) and Social Activities Checklist (Cruice, 2001, in Worrall & Hickson, 2003). Demographic information was also collected. Descriptive statistics are presented and independent samples t tests were used to examine differences between the groups. Outcomes & Results: Participants with primarily mild to moderate aphasic impairment reported a considerable range of social contacts (5-51) and social activities (8-18). Many significant differences were evident between the two groups' social contacts and activities. On average, aphasic participants had nine fewer social contacts (mainly friend'' relationships) and three fewer social activities (mainly leisure'' activities) than their non-aphasic peers. The majority of controls were satisfied with their social activities, whereas the majority of aphasic participants were not and wanted to be doing more. There were some general similarities between the groups, in terms of range of social contacts, overall pattern of social relationships, and core social activities. Conclusions: Older people with chronic aphasia had significantly fewer social contacts and social activities than their peers. People with aphasia expressed a desire to increase the social activity of their lives. Given the importance of leisure activity and relationships with friends as well as family for positive well-being, speech and language therapists may direct their rehabilitation efforts towards two areas: (1) conversational partner programmes training friends to maintain these relationships; and (2) encouraging and supporting aphasic clients in leisure activities of their choice.

Designing channel incentives to overcome reseller rejection

As more and more products are distributed through independent channel resellers, suppliers find it increasingly difficult to craft highly motivational incentive packages. Instead, many suppliers' product lines are neglected by resellers in deference to more compatible incentive offers. This paper studies the many aspects of incentive rejection and incentive compatibility and prescribes a four-step, theory-based process to help suppliers craft attractive incentive programs. The process involves identifying resellers' performance needs, recognizing how each need suggests a different basis for incentive rejection, and designing an incentive package such that the incentives support specific reseller needs. Also, unique channel conditions are considered.

Use of complementary and alternative medicine and self-tests by coronary heart disease patients

Background: Coronary heart disease patients have to learn to manage their condition to maximise quality of life and prevent recurrence or deterioration. They may develop their own informal methods of self-management in addition to the advice they receive as part of formal cardiac rehabilitation programmes. This study aimed to explore the use of complementary and alternative medicines and therapies (CAM), self-test kits and attitudes towards health of UK patients one year after referral to cardiac rehabilitation. Method: Questionnaire given to 463 patients attending an assessment clinic for 12 month follow up in four West Midlands hospitals. Results: 91.1% completed a questionnaire. 29.1% of patients used CAM and/or self-test kits for self-management but few (8.9%) used both methods. CAM was more often used for treating other illnesses than for CHD management. Self-test kit use (77.2%,) was more common than CAM (31.7%,) with BP monitors being the most prevalent (80.0%). Patients obtained self-test kits from a wide range of sources, for the most part (89.5%) purchased entirely on their own initiative. Predictors of self-management were post revascularisation status and higher scores on 'holism', 'rejection of authority' and 'individual responsibility'. Predictors of self-test kit use were higher `holism' and 'individual responsibility' scores. Conclusion: Patients are independently using new technologies to monitor their cardiovascular health, a role formerly carried out only by healthcare practitioners. Post-rehabilitation patients reported using CAM for self-management less frequently than they reported using self-test kits. Reports of CAM use were less frequent than in previous surveys of similar patient groups. Automatic assumptions cannot be made by clinicians about which CHD patients are most likely to self-manage. In order to increase trust and compliance it is important for doctors to encourage all CHD patients to disclose their self-management practices and to continue to address this in follow up consultations.

Implications of query caching for JXTA peers

This dissertation studies the caching of queries and how to cache in an efficient way, so that retrieving previously accessed data does not need any intermediary nodes between the data-source peer and the querying peer in super-peer P2P network. A precise algorithm was devised that demonstrated how queries can be deconstructed to provide greater flexibility for reusing their constituent elements. It showed how subsequent queries can make use of more than one previous query and any part of those queries to reconstruct direct data communication with one or more source peers that have supplied data previously. In effect, a new query can search and exploit the entire cached list of queries to construct the list of the data locations it requires that might match any locations previously accessed. The new method increases the likelihood of repeat queries being able to reuse earlier queries and provides a viable way of by-passing shared data indexes in structured networks. It could also increase the efficiency of unstructured networks by reducing traffic and the propensity for network flooding. In addition, performance evaluation for predicting query routing performance by using a UML sequence diagram is introduced. This new method of performance evaluation provides designers with information about when it is most beneficial to use caching and how the peer connections can optimize its exploitation.

Trained Neural Network Characterizing Variables for Predicting Organic Retention by Nanofiltration Membranes

Many organic compounds cause an irreversible damage to human health and the ecosystem and are present in water resources. Among these hazard substances, phenolic compounds play an important role on the actual contamination. Utilization of membrane technology is increasing exponentially in drinking water production and waste water treatment. The removal of organic compounds by nanofiltration membranes is characterized not only by molecular sieving effects but also by membrane-solute interactions. Influence of the sieving parameters (molecular weight and molecular diameter) and the physicochemical interactions (dissociation constant and molecular hydrophobicity) on the membrane rejection of the organic solutes were studied. The molecular hydrophobicity is expressed as logarithm of octanol-water partition coefficient. This paper proposes a method used that can be used for symbolic knowledge extraction from a trained neural network, once they have been trained with the desired performance and is based on detect the more important variables in problems where exist multicolineality among the input variables.

What will the boss think? The impression management implications of supportive relationships with star and project peers

Although impression management scholars have identified a number of tactics for influencing supervisor evaluations, most of those tactics represent supervisor-targeted behaviors. This study examines the degree to which employees form supportive relationships with peers for impression management purposes. In so doing, we explore this intriguing question: Will employees gain more from forming supportive relationships with stars (i.e., top performers who are on the fast track in the organization) or projects (i.e., works in progress who need help and refinement to perform well)? We examined this question in 2 field studies. Study 1 included 4 sources and 2 time periods; Study 2 included 2 sources and 3 time periods. The results showed that supportive relationships with both stars and projects seemed to represent impression management opportunities, insofar as they predicted supervisor positive affect and perceptions of employee promotability. Impression management motives only predicted supportive relationships with stars, however, not projects. Relationships with projects were driven by prosocial motives not concerns about managing images. We discuss the practical and theoretical implications of our results for the managing of impressions and peer relationships

A study of moderating influences of adolescent alcohol drinking conditioned by perception of peer alcohol drinking

Despite a long history of prevention efforts and federal laws prohibiting the consumption of alcohol for those below the age of 21 years, underage drinking continues at both a high prevalence rate and high incidence rate. The purpose of this research study is to explain underage drinking of alcohol conditioned by perception of peer drinking. An acquisition model is conjectured and then a relationship within the model is explained with a national sample of students. From a developmental perspective, drinking alcohol is acquired in a reasonably ordered fashion that reflects the influences over time of the culture, family, and peers. The study measures perceptions of alcohol drinking during early adolescence when alcohol use begins the maintenance phase of the behavior. The correlation between drinking alcohol and perception of classmate drinking can be described via social learning theory. Simultaneously the moderating effects of grade level, gender, and race/ethnicity are used to explain differences between groups. Multilevel logistic regression was used to analyze the relations. The researcher found support for an association between adolescent drinking and perceptions of classmate drinking. Gender and grade level moderated the relation. African-Americans consistently demonstrated less drinking and less perception of classmate drinking than either whites or other students not white nor African-American. The importance of a better understanding of the process of acquiring drinking behaviors is discussed in relation to future research models with longitudinal data. ^

Sense making by middlemanagement

Aanleiding voor het onderzoek Deze scriptie sluit aan bij de afstudeerkring “effectieve verandermanagers”. Aanleiding voor dit onderzoek was de brede vraag “Wat onderscheidt een effectieve veranderingsmanager op het middenniveau in organisaties van een minder effectieve bij het implementeren van veranderingen?” Binnen deze brede vraag past de centrale vraagstelling in dit onderzoek: “Welke neerwaartse activiteiten oefenen middenmanagers uit in een sensemakingproces tijdens een verandering?“ Middenmanager Allereerst definiëren we het begrip ‘middenmanager’. De middenmanager bevindt zich op een kruispunt: In de verticale lijn tussen het topmanagement en de werkvloer, op de horizontale lijn tussen de diverse afdelingen (Nonaka,1994). Ten behoeve van mijn onderzoek sluit ik mij aan bij de positionering van Huy (2001). Hij plaatst de middenmanager 2 lagen onder de CEO en 1 laag boven lijnmedewerkers en professionals. In een veranderingsproces heeft de middenmanager verschillende rollen te vervullen. Deze verschillende rollen zijn, onder anderen, beschreven door Huy (2001) en Quinn (1998). Zij noemen: entrepreneur, communicator en therapeut, stimulator, mentor, innovator, bemiddelaar, producent, bestuurder, coördinator, controleur. De onderzoekers zijn het er over eens dat de middenmanager moet balanceren en doseren in de verschillende rollen om effectief te kunnen zijn in een veranderingsproces. Sensemakingproces Dit onderzoek probeert meer kennis te genereren over welke neerwaartse activiteiten middenmanagers uitoefenen gedurende een sensemakingproces tijdens een verandering. We definiëren het begrip ‘sensemakingproces’. Het sensemakingproces vindt plaats als mensen geconfronteerd worden met boodschappen of gebeurtenissen die nieuw zijn. Door met deze nieuwe informatie te kijken naar de bestaande werkelijkheid, is een bewustwording op gang geholpen die kan leiden tot verandering. Er is nog weinig onderzoek gedaan naar de activiteiten (wat doen middenmanagers op dagelijkse basis) van middenmanagers in sensemakingprocessen. Rouleau & Balogun (2007) hebben dat wel onderzocht en onderscheiden de volgende vier sensegivingactiviteiten: het uitrollen van netwerken; het distribueren van gedachten door het voeren van gesprekken; het identificeren van sociale en culturele systemen. Relevantie onderzoek De externe validiteit van het hierboven genoemde onderzoek van Rouleau & Balogun (2007) is echter beperkt, doordat deze is uitgevoerd onder een kleine populatie in Canada en het Verenigd Koninkrijk. Mijn onderzoek wil een bijdrage leveren aan de toename van de externe validiteit door te verifiëren of de neerwaartse activiteiten van de middenmanager die gevonden zijn in het onderzoek van Rouleau & Balogun (2007) middels een andere onderzoeksmethode en met een andere onderzoekspopulatie (de Nederlandse zorginstelling Tactus). Wat betreft de praktische relevantie kan gezegd worden dat mijn onderzoek meer inzicht geeft aan de middenmanagers in welke activiteiten zij uitvoeren of zouden kunnen uitvoeren. Zij kunnen zich bewust worden van hun mogelijkheden om invloed uit te oefenen op het sensemakingproces van hun medewerkers. Ik verwacht daarmee hun effectiviteit te vergroten. Centrale vraag en deelvragen Bij de centrale vraag kunnen de volgende deelvragen geformuleerd worden: 1. Wat is de rol van middenmanagers in een sensemakingproces tijdens een verandering? 2. Zijn de neerwaartse sensemakingactiviteiten van middenmanagers (uit de studie van Rouleau & Balogun, 2007) ook te identificeren zijn binnen één Nederlandse GGZ-stichting? 3. Zijn er andere neerwaartse sensemakingactiviteiten van middenmanagers te identificeren? Conceptuele model Het model dat de basis is voor de beantwoording van de tweede en derde deelvraag, is gebaseerd op de literatuur. In dit model worden de sensemakingactiviteiten van de middenmanager als een onafhankelijke variabele gezien die direct invloed heeft op het sensemakingproces binnen het team. Daarbij kunnen we enkele mediërende en modererende factoren onderscheiden. Als modererende factor noemen we, ten eerste, de mate waarin voor het teamlid het persoonlijke triggerpoint bereikt is. Hoe dichter genaderd, hoe meer kans op verandering bij dit teamlid (Kloosterboer, 2008). Ten tweede noemen we het sneeuwbaleffect van de positieve feedback (Kelman, 2005): hoe verder in het proces, hoe meer kans op verandering. Tenslotte noemen we als modererende factor het emotiemanagement van de middenmanager. Hoe meer de middenmanager in staat is de balans te vinden, hoe meer kans op verandering (Huy, 2002). Als mediërende factor kunnen we de horizontale sensegiving noemen, ofwel de sensegiving door peers (Balogun & Johnson, 2005). Deze sensegiving kan, los van de sensemakingactiviteiten van de manager een geheel eigen verandering op gang brengen. Het kan dus gezien worden als (een deel van) de verklaring voor het sensemakingproces binnen het team. Dit onderzoek beperkt zich tot het bestuderen van de sensemakingactiviteiten van de middenmanager en hun effect op het sensemakingproces binnen het team. In het onderzoek worden de modererende factoren en de mediërende factor dus niet meegenomen. Onderzoeksopzet Het onderzoek is opgesteld als multiple-case design, toetsend onderzoek. Toetsend, omdat de externe validering van de neerwaartse sensemakingactiviteiten van de middenmanager nog laag is. Het multiple-case design biedt de mogelijkheid om cases met elkaar te vergelijken en bredere steun te vinden voor de geformuleerde proposities. De voorgenomen bronnen waren een (één op één) interview met acht middenmanagers, een groepsinterview met meerdere medewerkers per middenmanager en documenten. De focus in alle interviews was de middenmanager en diens sensemakingactiviteiten. De opgevraagde en aangeleverde documenten zijn echter geen adequate bron van informatie gebleken. Resultaten De eerste deelvraag is beantwoord middels literatuurstudie. De onderzoekers zijn het er over eens dat de middenmanager moet balanceren en doseren in de verschillende rollen om effectief te kunnen zijn in een veranderingsproces. De tweede en derde deelvraag werden beantwoord middels een multiple-case design onderzoek. De resultaten uit dit onderzoek laten zien dat de neerwaartse sensemakingactiviteiten uit de studie van Rouleau & Balogun (2007), inderdaad gevonden werden binnen de genoemde GGZ-stichting. De hypothese is daarmee geverifieerd. De derde conclusie is dat er geen andere neerwaartse sensemakingactiviteiten van middenmanagers zijn geïdentificeerd. Door de verkregen informatie over de vier sensemakingactiviteiten van middenmanager terug te brengen naar handelingsniveau, is zichtbaar geworden dat er verschillen zijn tussen de middenmanagers. De handelingen in gezamenlijkheid leidden wel tot de vier sensemakingactiviteiten. Discussie De casestudie heeft geen nieuwe activiteiten aangetoond. Dat maakt de definiëring van het begrip steviger. Door de vier sensemakingactiviteiten (Rouleau & Balogun, 2007) op een derde niveau op te delen in kleinere eenheden, draagt deze casestudie tevens bij aan een nadere definiëring van het begrip ‘neerwaartse sensemakingactiviteiten van de middenmanager’. Door de verduidelijking van het begrip is kwantitatief onderzoek beter mogelijk, waardoor nu ook causale verbanden tussen de neerwaartse sensemakingactiviteiten van de middenmanager en de sensemaking bij de medewerkers gemaakt kunnen worden. Aanbevelingen In een vervolgonderzoek zou het conceptuele model deels of geheel onderzocht kunnen worden. Met een dergelijk onderzoek, of meerdere onderzoeken zou meer duidelijkheid kunnen komen over de mate van invloed van de mediërende factoren en modererende factor op de sensemaking. Aanbeveling voor verder onderzoek is om de onderzoeksmethode te variëren of uit te breiden met bijvoorbeeld participerende observatie. Dan zou waarneming kunnen plaatsvinden vanuit het perspectief van een betrokkene (Yin, 2003). Een andere methode om de activiteiten beter te inventariseren is het laten bijhouden door managers van hun sensemakingactiviteiten. Een bijkomende propositie die dit onderzoek oplevert, is dat de relatie tussen al dan niet hebben van onbewuste kennis en het beschikken over ervaring als leidinggevende niet gelegd kan worden. Deze propositie zou verder onderzocht kunnen worden.

Consequences of Influence Tactics Used With Subordinates, Peers, and the Boss

A field study was conducted to discover how a manager's use of 9 different influence tactics is related to target task commitment and the manager's effectiveness. The variables were measured with a questionnaire filled out by subordinates, peers, and the boss of each manager. The most effective tactics were rational persuasion, inspirational appeal, and consultation; the least effective tactics were pressure, coalition, and legitimating. Ingratiation and exchange were moderately effective for influencing subordinates and peers but were not effective for influencing superiors. Inspirational appeal, ingratiation, and pressure were used most in a downward direction; personal appeal, exchange, and legitimating were used most in a lateral direction; coalitions were used most in lateral and upward directions; and rational persuasion was used most in an upward direction.

NK Cells of Kidney Transplant Recipients Display an Activated Phenotype that Is Influenced by Immunosuppression and Pathological Staging

To explore phenotype and function of NK cells in kidney transplant recipients, we investigated the peripheral NK cell repertoire, capacity to respond to various stimuli and impact of immunosuppressive drugs on NK cell activity in kidney transplant recipients. CD56(dim) NK cells of kidney transplanted patients displayed an activated phenotype characterized by significantly decreased surface expression of CD16 (p=0.0003), CD226 (p<0.0001), CD161 (p=0.0139) and simultaneously increased expression of activation markers like HLA-DR (p=0.0011) and CD25 (p=0.0015). Upon in vitro stimulation via Ca++-dependent signals, down-modulation of CD16 was associated with induction of interferon (IFN)-gamma expression. CD16 modulation and secretion of NFAT-dependent cytokines such as IFN-gamma, TNF-alpha, IL-10 and IL-31 were significantly suppressed by treatment of isolated NK cells with calcineurin inhibitors but not with mTOR inhibitors. In kidney transplant recipients, IFN-gamma production was retained in response to HLA class I-negative target cells and to non-specific stimuli, respectively. However, secretion of other cytokines like IL-13, IL-17, IL-22 and IL-31 was significantly reduced compared to healthy donors. In contrast to suppression of cytokine expression at the transcriptional level, cytotoxin release, i.e. perforin, granzyme A/B, was not affected by immunosuppression in vitro and in vivo in patients as well as in healthy donors. Thus, immunosuppressive treatment affects NK cell function at the level of NFAT-dependent gene expression whereby calcineurin inhibitors primarily impair cytokine secretion while mTOR inhibitors have only marginal effects. Taken together, NK cells may serve as indicators for immunosuppression and may facilitate a personalized adjustment of immunosuppressive medication in kidney transplant recipients.